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In Duchenne muscular dystrophy (DMD), the activation of proinflammatory and metabolic cellular pathways in skeletal muscle cells is an inherent characteristic. Synthetic glucocorticoid intake counteracts the majority of these mechanisms. However, glucocorticoids induce burdensome secondary effects, including hypertension, arrhythmias, hyperglycemia, osteoporosis, weight gain, growth delay, skin thinning, cushingoid appearance, and tissue-specific glucocorticoid resistance. Hence, lowering the glucocorticoid dosage could be beneficial for DMD patients. A more profound insight into the major cellular pathways that are stabilized after synthetic glucocorticoid administration in DMD is needed when searching for the molecules able to achieve similar pathway stabilization. This review provides a concise overview of the major anti-inflammatory pathways, as well as the metabolic effects of glucocorticoids in the skeletal muscle affected in DMD. The known drugs able to stabilize these pathways, and which could potentially be combined with glucocorticoid therapy as steroid-sparing agents, are described. This could create new opportunities for testing in DMD animal models and/or clinical trials, possibly leading to smaller glucocorticoids dosage regimens for DMD patients.

Long non-coding RNAs (lncRNAs) can exhibit cell-type and cancer-type specific expression profiles, making them highly attractive as therapeutic targets. Pan-cancer RNA sequencing data revealed broad expression of the SAMMSON lncRNA in uveal melanoma (UM), the most common primary intraocular malignancy in adults. Currently, there are no effective treatments for UM patients with metastatic disease, resulting in a median survival time of 6–12 months. We aimed to investigate the therapeutic potential of SAMMSON inhibition in UM. Antisense oligonucleotide (ASO)-mediated SAMMSON inhibition impaired the growth and viability of a genetically diverse panel of uveal melanoma cell lines. These effects were accompanied by an induction of apoptosis and were recapitulated in two uveal melanoma patient derived xenograft (PDX) models through subcutaneous ASO delivery. SAMMSON pulldown revealed several candidate interaction partners, including various proteins involved in mitochondrial translation. Consequently, inhibition of SAMMSON impaired global, mitochondrial and cytosolic protein translation levels and mitochondrial function in uveal melanoma cells. The present study demonstrates that SAMMSON expression is essential for uveal melanoma cell survival. ASO-mediated silencing of SAMMSON may provide an effective treatment strategy to treat primary and metastatic uveal melanoma patients.

Growth differentiation factor 15 (GDF-15) is a stress-induced transforming growth factor-β superfamily cytokine with versatile functions in human health. Elevated GDF-15 blood levels associate with multiple pathological conditions, and are currently extensively explored for diagnosis, and as a means to monitor disease progression and evaluate therapeutic responses. This review analyzes GDF-15 in human conditions specifically focusing on its association with muscle manifestations of sarcopenia, mitochondrial myopathy, and autoimmune and viral myositis. The use of GDF-15 as a widely applicable health biomarker to monitor muscle disease is discussed, and its potential as a therapeutic target is explored.

Muscle atrophy is an active process controlled by specific transcriptional programs, in which muscle mass is lost by increased protein degradation and/or decreased protein synthesis. This review explores the involvement of Toll-like receptors (TLRs) in the muscle atrophy as it is observed in muscular dystrophies, disorders characterized by successive bouts of muscle fiber degeneration and regeneration in an attempt to repair contraction-induced damage. TLRs are defense receptors that detect infection and recognize self-molecules released from damaged cells. In muscular dystrophies, these receptors become over-active, and are firmly involved in the sustained chronic inflammation exhibited by the muscle tissue, via their induction of pro-inflammatory cytokine expression. Taming the exaggerated activation of TLR2/4 and TLR7/8/9, and their downstream effectors in particular, comes forward as a therapeutic strategy with potential to slow down disease progression.

The idiopathic inflammatory myopathies (IIM) constitute a heterogeneous group of chronic disorders that include dermatomyositis (DM), polymyositis (PM), sporadic inclusion body myositis (IBM) and necrotizing autoimmune myopathy (NAM). They represent distinct pathological entities that, most often, share predominant inflammation in muscle tissue. Many of the immunopathogenic processes behind the IIM remain poorly understood, but the crucial role of cytokines as essential regulators of the intramuscular build-up of inflammation is undisputed. This review describes the extensive cytokine network within IIM muscle, characterized by strong expression of Tumor Necrosis Factors (TNFα, LTβ, BAFF), Interferons (IFNα/β/γ), Interleukins (IL-1/6/12/15/18/23) and Chemokines (CXCL9/10/11/13, CCL2/3/4/8/19/21). Current therapeutic strategies and the exploration of potential disease modifying agents based on manipulation of the cytokine network are provided. Reported responses to anti-TNFα treatment in IIM are conflicting and new onset DM/PM has been described after administration of anti-TNFα agents to treat other diseases, pointing to the complex effects of TNFα neutralization. Treatment with anti-IFNα has been shown to suppress the IFN type 1 gene signature in DM/PM patients and improve muscle strength. Beneficial effects of anti-IL-1 and anti-IL-6 therapy have also been reported. Cytokine profiling in IIM aids the development of therapeutic strategies and provides approaches to subtype patients for treatment outcome prediction.

Background/Objectives: The progressive life-limiting disorder Duchenne muscular dystrophy (DMD) arises from the absence of dystrophin protein at the muscle cell membrane, which leads to progressive contraction-induced damage. Despite the advancements in molecular therapies aimed at reintroducing (partially functional) dystrophin in patients, a cure for DMD remains elusive. Taurine supplements have been proposed as a potential supportive treatment for DMD, based upon encouraging results in the mouse model mdx. Methods: In a previous study, we observed improvements in skeletal muscle histology and a reduction in the expression of inflammatory markers after short-term treatment with 4.6 g taurine per kg body weight during the initial stages of the disease. In this follow-up study, we examined cell death and tissue restoration protein levels in mdx subjected to the same treatment regimen, utilizing proteome arrays, Western blotting, and immunofluorescence. Results: We report that, while the levels of apoptotic and autophagic proteins remained constant, selective and significant decrease in receptor-interacting Serine/Threonine protein kinase 1 (RIP1) levels could be observed in taurine-treated mdx compared to untreated mdx. RIP1 was immunolocalized to muscle fibers, with faint homogeneous staining in age-matched healthy controls shifting to a heterogeneous staining pattern in mdx, the latter diminishing with taurine treatment. Conclusions: Given its role as a molecular switch in cell fate decisions, the observed taurine-induced downregulation of RIP1 supports the potential beneficial effects of the osmolyte in mdx.

Taurine (2-aminoethanesulfonic acid) is required for ensuring proper muscle functioning. Knockout of the taurine transporter in mice results in low taurine concentrations in the muscle and associates with myofiber necrosis and diminished exercise capacity. Interestingly, regulation of taurine and its transporter is altered in the mdx mouse, a model for Duchenne Muscular Dystrophy (DMD). DMD is a genetic disorder characterized by progressive muscle degeneration and weakness due to the absence of dystrophin from the muscle membrane, causing destabilization and contraction-induced muscle cell damage. This review explores the physiological role of taurine in skeletal muscle and the consequences of a disturbed balance in DMD. Its potential as a supportive treatment for DMD is also discussed. In addition to genetic correction, that is currently under development as a curative treatment, taurine supplementation has the potential to reduce muscle inflammation and improve muscle strength in patients.

The sporadic form of inclusion body myositis (IBM) is the most common late-onset myopathy. Its complex pathogenesis includes degenerative, inflammatory and mitochondrial aspects. However, which of those mechanisms are cause and which effect, as well as their interrelations, remain partly obscured to this day. In this review the nature of the mitochondrial dysregulation in IBM muscle is explored and comparison is made with other muscle disorders. Mitochondrial alterations in IBM are evidenced by histological and serum biomarkers. Muscular mitochondrial dynamics is disturbed, with deregulated organelle fusion leading to subsequent morphological alterations and muscle displays abnormal mitophagy. The tissue increases mitochondrial content in an attempt to compensate dysfunction, yet mitochondrial DNA (mtDNA) alterations and mild mtDNA depletion are also present. Oxidative phosphorylation defects have repeatedly been shown, most notably a reduction in complex IV activities and levels of mitokines and regulatory RNAs are perturbed. Based on the cumulating evidence of mitochondrial abnormality as a disease contributor, it is therefore warranted to regard IBM as a mitochondrial disease, offering a feasible therapeutic target to be developed for this yet untreatable condition.

Duchenne muscular dystrophy (DMD), the severest form of muscular dystrophy, is characterized by progressive muscle weakness with fatal outcomes most often before the fourth decade of life. Despite the recent addition of molecular treatments, DMD remains a disease without a cure, and the need persists for the development of supportive therapies aiming to help improve patients’ quality of life. This review focuses on the therapeutical potential of amino acid and derivative supplements, summarizing results obtained in preclinical studies in murine disease models. Several promising compounds have emerged, with L-arginine, N-acetylcysteine, and taurine featuring among the most intensively investigated. Their beneficial effects include reduced inflammatory, oxidative, fibrotic, and necrotic damage to skeletal muscle tissues. Improvement of muscle strength and endurance have been reported; however, mild side effects have also surfaced. More explorative, placebo-controlled and long-term clinical trials would need to be conducted in order to identify amino acid formulae that are safe and of true benefit to DMD patients.